Dendritic Cells and Type 2 Inflammation
Dendritic cells (DCs) are specialised innate immune cells that play a key role in initiation and direction of adaptive immunity against diverse immune challenges. However, relatively little is known about precisely how DCs become activated and function in Type 2 settings, either during parasitic helminth infection or following exposure to allergens. Using a combination of in vitro, in vivo and ex vivo model systems, we have shown that DCs responding to helminths display an unusual, low level, activation phenotype distinct from that ordinarily seen during viral or bacterial infection. Irrespective of this, we have demonstrated that DCs are both sufficient and necessary for induction of Type 2 immunity against several helminth species.
Although DCs are clearly centrally involved in coordination of the immune response during Type 2 inflammation, the specific mechanism(s) by which they direct Th2 polarisation remain poorly understood. We have recently discovered that epigenetic regulation of DCs, via the action of the methyl-binding protein Mbd2, is vital for optimal induction and development of Type 2 inflammation against either helminths or allergens. This reveals that epigenetic mechanisms can play an essential role in controlling DC activation and function, and identifies methyl binding proteins and/or genes that they regulate as exciting new targets for therapeutic modulation of Type 2 Immunity.
We have also begun to apply our understanding of immune mechanisms at play in helminth infection to pulmonary allergic inflammation, as well as to initiate studies using human DCs to complement and inform our murine work. Our expertise in isolation of delicate and rare cells from tissues, and multi-parameter flow cytometry, provides the opportunity to tackle the formidable technical challenge of clearly defining the activation and function of DCs and other immune cells during both murine and human pulmonary inflammation, where cell numbers are often extremely limited. Ongoing projects in this area include the investigation of mechanisms that control activation and renewal of airway macrophages and DCs, and mechanisms of cross-talk between pulmonary epithelial cells and DCs, during Type 2 inflammation.
Our goal is to transform fundamental understanding of the cellular and molecular mechanisms by which Type 2 responses are initiated, maintained and regulated, to enable rational design of innovative therapies targeting cells or their products to combat Type 2 inflammatory disease.
Peter C. Cook, Heather Owen, Aimee M. Deaton, Jessica G. Borger, Sheila L. Brown, Thomas Clouaire, Gareth-Rhys Jones, Lucy H. Jones, Rachel J. Lundie, Angela K. Marley, Vicky L. Morrison, Alexander T. Phythian-Adams, Elizabeth Wachter, Lauren M. Webb, Tara E. Sutherland, Graham D. Thomas, John R. Grainger, Jim Selfridge, Andrew N.J. McKenzie, Judith E. Allen, Susanna C. Fagerholm, Rick M. Maizels, Alasdair C. Ivens, Adrian Bird and Andrew S. MacDonald. A dominant role for the methyl-CpG binding domain protein Mbd2 in controlling Th2 induction by dendritic cells. 2015. Nature Communications. 6: 6920.
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